Neuromodulatory effects and targets of the SCFAs and gasotransmitters produced by the human symbiotic microbiota.

The symbiotic gut microbiota plays an important role in the development and homeostasis of the host organism. Its physiological, biochemical, behavioral, and communicative effects are mediated by multiple low molecular weight compounds. Recent data on small molecules produced by gut microbiota in mammalian organisms demonstrate the paramount importance of these biologically active molecules in terms of biology and medicine. Many of these molecules are pleiotropic mediators exerting effects on various tissues and organs. This review is focused on the functional roles of gaseous molecules that perform neuromediator and/or endocrine functions. The molecular mechanisms that underlie the effects of microbial fermentation-derived gaseous metabolites are not well understood. It is possible that these metabolites produce their effects via immunological, biochemical, and neuroendocrine mechanisms that involve endogenous and microbial modulators and transmitters; of considerable importance are also changes in epigenetic transcriptional factors, protein post-translational modification, lipid and mitochondrial metabolism, redox signaling, and ion channel/gap junction/transporter regulation. Recent findings have revealed that interactivity among such modulators/transmitters is a prerequisite for the ongoing dialog between microbial cells and host cells, including neurons. Using simple reliable methods for the detection and measurement of short-chain fatty acids (SCFAs) and small gaseous molecules in eukaryotic tissues and prokaryotic cells, selective inhibitors of enzymes that participate in their synthesis, as well as safe chemical and microbial donors of pleiotropic mediators and modulators of host intestinal microbial ecology, should enable us to apply these chemicals as novel therapeutics and medical research tools.

Epigenomic programing: a future way to health?

It is now generally accepted that the 'central genome dogma' (i.e. a causal chain going from DNA to RNA to proteins and downstream to biological functions) should be replaced by the 'fluid genome dogma', that is, complex feed-forward and feed-back cycles that interconnect organism and environment by epigenomic programing - and reprograming - throughout life and at all levels, sometimes also down the generations. The epigenomic programing is the net sum of interactions derived from own metabolism and microbiota as well as external factors such as diet, pharmaceuticals, environmental compounds, and so on. It is a growing body of results indicating that many chronic metabolic and degenerative disorders and diseases - often called 'civilization diseases' - are initiated and/or influenced upon by non-optimal epigenomic programing, often taking place early in life. In this context, the first 1,000 days of life - from conception into early infancy - is often called the most important period of life. The following sections present some major mechanisms for epigenomic programing as well as some factors assumed to be of importance. The need for more information about own genome and metagenome, as well as a substantial lack of adequate information regarding dietary and environmental databases are also commented upon. However, the mere fact that we can influence epigenomic health programing opens up the way for prophylactic and therapeutic interventions. The authors underline the importance of creating a 'Human Gut Microbiota and Epigenomic Platform' in order to facilitate interdisciplinary collaborations among scientists and clinicians engaged in host microbial ecology, nutrition, metagenomics, epigenomics and metabolomics as well as in disease epidemiology, prevention and treatment.

Metabiotics: novel idea or natural development of probiotic conception.

Traditionally, probiotics on the base of live microorganisms are considered to be both beneficial and safe. Unfortunately, their effects may have short-term success or are absent or uncertain. Some symbiotic (probiotic) microorganisms with known beneficial health affects may cause opportunistic infections, increase incidence of allergic sensitization and autoimmune disorders, produce microecological imbalance, modify gene expression, transfer antibiotic resistant and virulence genes, cause disorders in epigenome and genome integrity, induce chromosomal DNA damage, and activate signaling pathways associated with cancer and other chronic diseases. The commercially available probiotics should be considered as a first generation means of correcting microecological disorders. Further, their development will include the selection of natural metabiotics and/or working out the synthetic (or semi-synthetic) metabiotics that will be analogies or improved copies of natural bioactives, produced by symbiotic (probiotic) microorganisms. Metabiotics are the structural components of probiotic microorganisms and/or their metabolites and/or signaling molecules with a determined (known) chemical structure that can optimize host-specific physiological functions, regulator, metabolic and/or behavior reactions connected with the activity of host indigenous microbiota. Metabiotics have some advantages because of their exact chemical structure, well dosed, very safe and long shelf-life. Thus, now metabiotics should not consider myth; they are the result of the natural evolution of probiotic conception.

Probiotics and Psychobiotics: the Role of Microbial Neurochemicals.

In light of recent data, microorganisms should be construed as organisms that are capable of communication and collective behaviors. Microbial communication signals are involved both in interactions among microbial cells within microbial social systems, including the human body-inhabiting microconsortium, and the dialog between the microbiota and the host organism. The microbiota inhabits various niches of the host organism, especially the gastrointestinal (GI) tract. Microorganisms release diverse signal molecules and, in addition, specifically respond to host signals. This enables them to constantly interact with the nervous system including the brain and the immune system of the host organism. Evolutionarily conserved signals that are involved in the communication between microbiota and the host include neuroactive substances (neurochemicals) such as peptides, amino acids, biogenic amines, short-chain fatty acids, and gaseous substances. This ongoing dialog may either stabilize the host's physical and mental health state or, alternatively, cause serious health problems. Attempts are made to correct imbalances in the brain-gut-microbiota axis with probiotics including their subgroup called psychobiotics that release neuroactive substances directly influencing the human brain, psyche, and behavior. A number of recent review works address the microbiota-host system and its communication signals. Some of the publications focus on the involvement of neurochemicals in the bidirectional communication within the host-microbiota system. However, this work concentrates on the impact of bacterial cell components, metabolites, and signal molecules as promising alternatives to the currently widespread probiotics that have both advantages and disadvantages. Such biologically active agents of microbial origin are referred to as postbiotics or, alternatively, metabiotics (the term preferred in this work).

Role of Neurochemicals in the Interaction between the Microbiota and the Immune and the Nervous System of the Host Organism.

This work is concerned with the role of evolutionary conserved substances, neurotransmitters, and neurohormones, within the complex framework of the microbial consortium-immune system-nervous system axis in the human or animal organism. Although the operation of each of these systems per se is relatively well understood, their combined effects on the host organism still await further research. Drawing on recent research on host-produced and microbial low-molecular-weight neurochemicals such as biogenic amines, amino acids, and short-chain fatty acids (SCFAs), we suggest that these mediators form a part of a universal neurochemical "language." It mediates the whole gamut of harmonious and disharmonious interactions between (a) the intestinal microbial consortium, (b) local and systemic immune cells, and (c) the central and peripheral nervous system. Importantly, the ongoing microbiota-host interactivity is bidirectional. We present evidence that a large number of microbially produced low-molecular-weight compounds are identical or homologous to mediators that are synthesized by immune or nervous cells and, therefore, can bind to the corresponding host receptors. In addition, microbial cells specifically respond to host-produced neuromediators/neurohormones because they have adapted to them during the course of many millions of years of microbiota-host coevolution. We emphasize that the terms "microbiota" and "microbial consortium" are to be used in the broadest sense, so as to include, apart from bacteria, also eukaryotic microorganisms. These are exemplified by the mycobiota whose role in the microbial consortium-immune system-nervous system axis researchers are only beginning to elucidate. In light of the above, it is imperative to reform the current strategies of using probiotic microorganisms and their metabolites for treating and preventing dysbiosis-related diseases. The review demonstrates, in the example of novel probiotics (psychobiotics), that many target-oriented probiotic preparations produce important side effects on a wide variety of processes in the host organism. In particular, we should take into account probiotics' capacity to produce mediators that can considerably modify the operation of the microecological, immune, and nervous system of the human organism.